Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
  • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
  • C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
  • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof

Definitions

• This invention relates to condensed benzene derivatives, a medicine for treating or preventing cerebral circulation disorder, cerebral metabolism disorder, and memory disturbance comprising the same, and intermediates for preparing the same.
• Senile dementia caused by such cerebral disorders as cerebrovascular disorder, cerebral circulation disorder, cerebral metabolism disorder, and memory disturbance has become a social problem in the society with prolonged life-­span. Development of medicines useful for treating or preventing these diseases are thus desired.
• Prolyl endopeptidase inhibitors are known as exhibiting anti-amnesic activity, since prolyl endopeptidase hydrolyzes and inactivates neuropeptides including proline in brains such as vasopressin [European Patent Publication No. 232849, Folia Pharmacologica Japonica, 89 , 323 (1987), and id., 89 , 243 (1987)].
• the present inventors have undertaken extensive studies on various compounds in order to obtain a novel medicine for treating or preventing cerebral circulation disorder, cerebral metabolism disorder, and memory disturbance.
• a condensed benzene derivative represented by the following formula (I) exhibited both prolyl endopeptidase inhibitory activity, anti-hypoxic activity and anti-amnesic and cerebral circulation/metabolism improving activity at the same time. Such a finding has led to the completion of the present invention.
• an object of this invention is to provide a condensed benzene derivative represented by the following (I), wherein A represents a methylene, ethylene, or propylene group, B represents a methylene or ethylene group, m denotes an integer of 0-5, X and Y which may be same or different represent a methylene group or a sulfur atom, R1 represents a hydrogen atom, a carboxyl, lower alkyloxycarbonyl, hydroxymethyl, or formyl group, R2 represents a hydrogen atom, a halogen atom, a lower alkyl, lower alkoxy, nitro, or amino group, R3 represents a hydrogen atom or a lower alkyl group, and the dotted line may optionally be present; a medicine for treating or preventing cerebral circulation disorder, cerebral metabolism disorder, and memory disturbance comprising the condensed benzene derivative; and an intermediate for preparing the condensed benzene derivative.
• A represents a methylene, ethylene, or propylene
• a lower alkyl group in this invention is defined as linear or branched alkyl group having 1-6 carbon atoms. Specific examples of the lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, t-­butyl, and the like.
• a lower alkoxy group is defined as linear or branched alkoxy group having 1-6 carbon atoms. Specific examples are methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like.
• the compound of the present invention can be prepared, for example, according to the following reaction formula.
• D in compound (III) represents a halogen atom, a lower alkoxy group, or a hydroxyl group
• R4 in compounds II) and (IV) represents a hydrogen atom or a lower alkyl group
• E in compound (Ib) and (V) represents a lower alkyl group
• R1, R2, R3, X, Y, A, B, and m in several compounds have the same meanings defined for formula (I).
• An acid halide, ester, or carboxylic acid (III) is reacted with a cyclic amino acid compound (IV) in the presence or absence of a base to produce an N-substituted cyclic amino acid derivative (II).
• the compound III when D in formula (III) is a halogen atom or a lower alkoxy group, can be condensed with compound (IV). It is desirable to use a carbodiimide as a condensing agent when D in formula (III) is a hydroxyl group.
• a desirable base is sodium hydroxide, potassium hydroxide, or the like.
• reaction temperature is -20 to 200°C. Any solvent which does not involve in the reaction may be used.
• a condensation reaction of an N-substituted cyclic amino acid derivative (II) and thiazolidine or pyrrolidine produces the compound (Ia), which is a compound having a hydrogen atom for R1 in formula (I).
• a commonly used condensing agent can be used in the condensation reactions.
• Preferable condensing agents are carbodiimides such as WSC, WSC ⁇ HCl, DCC, or the like.
• Any solvents which are inert to the reaction can be used. Examples of preferable solvents are methylene chloride, chloroform, tetrahydrofuran, dioxane, and the like.
• the reaction temperature of -20 to 80°C, preferably of 0 to 40°C, is applied.
• condensation methods which are commonly employed, for example, the acid chloride method, the mixed anhydride method, or the like [Izumiya et al.; PEPTIDE GOUSEI NO KISO TO JIKKEN; Maruzen Publishing Co. (1985)] may also be used.
• the compound (1c), which is a compound having a carboxyl group for R1 in formula (I), can be prepared by hydrolyzing a compound of formula (1b).
• the compound (1d) which is a compound having a hydroxymethyl group for R1 in formula (I), can be prepared by reducing a compound of formula (1b).
• a borohydride such as sodium borohydride, lithium borohydride, zinc borohydride, potassium borohydride, or the like is preferable as a reducing agent.
• an alcohol such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, or the like, or an ether such as tetrahydrofuran, dioxane, or the like is preferably used.
• the compound (1e) which is a compound having a formyl group for R1 in formula (I)
• oxidizing agents are dimethyl sulfoxide, chromium trioxide-­pyridine complex, t-butyl chloro formate, silver oxide, manganese dioxide, and the like.
• the reaction is carried out in the presence or absence of an inert organic solvent such as methylene chloride, chloroform, benzene, or the like, at room temperature or with cooling.
• dimethyl sulfoxide When dimethyl sulfoxide is used as a oxidizing agent, it is desirable to use an activation agent such as sulfur trioxide-pyridine complex, oxalyl chloride, dicyclohexyl carbodiimide, or the like.
• an activation agent such as sulfur trioxide-pyridine complex, oxalyl chloride, dicyclohexyl carbodiimide, or the like.
• a cyclic amino acid compound (IV) of DL-, D, or L-configulation produces the corresponding compound (I) and N-substituted amino acid derivative (II) having DL-, D, or L-configulation.
• the configulation of each assymetric carbon atom can be either S or R.
• the present invention also includes mixtures S- and R-configuration isomers.
• a compound of formula (I) can also be prepared by the condensation reaction of a compound of the formula (III) and a compound of the formula (IX).
• the method of the condensation is the same as the above-mentioned condensation process for producing compounds of formula (I).
• the compound of the formula (IX) can be prepared according to the following reaction formula, wherein R5 is a protective group for an amino acid, B, X, Y, and R1, have the same meanings as defined previously.
• a cyclic amino acid compound (VI) and a cyclic amine (VII) is reacted to produce a compound (VIII).
• a compound (IX) is prepared by removing the protective group R5 from the compound (VIII).
• the compound (I) of the present invention prepared by the manner discussed above exhibits prolyl endopeptidase inhibitory activity, anti-hypoxic activity, and anti-amnesic activity at the same time, and is a highly safe compound. It is therefore useful as a medicine for treating or preventing cerebral circulation disorder, cerebral metabolism disorder, and memory disturbance.
• the compound of formula (I) of the present invention can be prepared in various dosing forms for oral or non-oral administration by formulating various pharmacologically acceptable carriers.
• this compound is appropriately formulated together with suitable additives, including excipients such as lactose, mannitol, corn starch, crystallized cellulose, etc., binders such as cellulose derivatives, gum arabic, gelatin, etc., disintegrators such as calcium carboxymethyl cellulose, etc., lubricants such as talc, magnesium stearate, etc., and the like.
• excipients such as lactose, mannitol, corn starch, crystallized cellulose, etc.
• binders such as cellulose derivatives, gum arabic, gelatin, etc.
• disintegrators such as calcium carboxymethyl cellulose, etc.
• lubricants such as talc, magnesium stearate, etc., and the like.
• solid formulations can also be prepared in enteric coated pills using a coating substrate such as hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate phthalate, methacrylate copolymer, or the like.
• Non-oral dosing forms include an injection, into which water, ethanol, glycerol, commonly used surface active agents, and the like may be formulated.
• the compound of formula (I) can also be prepared in a suppository using a suitable suppository substrate.
• the amount of dosage of the compound of formula (I) used may vary depending on the body weight, age, symptoms of the subject, the intended treatment effect, the manner by which it is administered, and the period of administration.
• a generally appropriate amount may be from 1 to 2,000 mg per day, preferably from 10 to 200 mg per day, with the frequency of administration being 1 to 3 times per day.
• a prolyl endopeptidase was prepared from canine brains according to the method of Yoshimoto et al. [J. Biochem., 94 , 325 (1983)].
• Buffer A 20 mM Tris-HCl buffer (pH 7.0)
• Buffer B Buffer A containing 0.1% gelatin, 1 mM EDTA, and 1 mM 2-mercaptoethanol
• the prolyl endopeptidase was dissolved in the Buffer B at a concentration of 0.4 unit/ml. This solution (50 ⁇ l) was added to 940 ⁇ l of the Buffer A, and the solution thus obtained was left at 37°C for 10 minutes (This solution is herein referred to as "Enzyme solution”). A mixed solution of 50 ⁇ l of the Buffer B and 940 ⁇ l of Buffer A was used as a "Correction solution".
• a test compound was dissolved in dimethylsulfoxide, and 10 ⁇ l of the solution was added to the Enzyme solution. The mixture was stirred and allowed to stand at 37°C for 10 minutes. Separately, 10 ⁇ l of dimethylsulfoxide was added to the Enzyme solution and was processed in the same manner. The solution thus obtained was served as a "Control solution”. The same procedure was carried out on the Correction solution.
• Enzyme activities were determined by subtracting the blank value, i.e., the absorbance measured on the Correction solution, from the absorbance of each of the sample solutions and of the Control solution.
• Inhibition potency (IC50) of the sample compound against prolyl endopeptidase was determined as the concentration of the compound (M) capable of inhibiting 50% of the enzyme activity of the control. The results are shown in Table 1. TABLE 1 Compounds Inhibition Potency, IC50 (M) Compound of Example 1 6.5 x 10 ⁇ 9 Compound of Example 3 7.9 x 10 ⁇ 9 Compound of Example 4 1.4 x 10 ⁇ 8 Compound of Example 5 2.2 x 10 ⁇ 8 Compound of Example 10 4.9 x 10 ⁇ 8 Compound of Example 14 1.8 x 10 ⁇ 8 Compound of Example 18 4.3 x 10 ⁇ 8 Compound of Example 22 6.2 x 10 ⁇ 9 Compound of Example 42 1.3 x 10 ⁇ 9 SUAM 1221 * 7.6 x 10 ⁇ 8 Aniracetam > 10 ⁇ 3 * The compound described in European Patent Publication No. 232849,
• mice Groups of ICR male mice (Charles River Co.), age 4 to 5 weeks, each group consisting of 10 mice and each mouse having been fasted for 24 hours, were used for the test. Mice were placed in a transparent desiccator (diameter: 19 cm, height: 30 cm) made of synthetic resin and having 2 valves, one at the upper portion and the other at the lower portion, for replacing the gas therein. A mixed gas (4% O2 + 96% N2) was fed from the upper valve at a rate of 10 l/min to measure the period of time until respiratory arrest took place for each mouse. The time measured was taken as the survival time.
• Each tested compound suspended in an solvent was intraperitoneally administered 30 minutes before the start of the mixed gas feeding.
• a group of mice to which only the solvent was intraperitoneally administered was used as a control.
• the anti-hypoxic activity was determined according to the following formula, The results are shown in Table 2.
• the compounds of this invention are superior to aniracetam, calcium hopantenate, idebenone, and SUAM 1221 (the compound described in European Patent Publication No. 232849), in their prolyl endopeptidase inhibitory activities against the prolyl endopeptidase from canine brain and anti-hypoxic activities.
• mice Groups of ICR male mice (Charles River Co.), age 4 to 5 weeks, each group consisting of 10 mice were used for the test. A dose of 300 mg/kg of each compound prepared in
• Examples 1-52 hereinbelow suspended in 5% gum arabic was intraperitoneally administered to each group of mice. No fatal problem in mice was observed during a period of 7 days.
• a colorless oil of ethyl 1-(2-indanylacetyl)-DL-­piperidin-2-ylcarboxylate was prepared in the same manner as in Reference Example 1, except that ethyl DL-­piperidin-2-ylcarboxylate was used instead of L-thioproline ethyl ester (yield: 51%).
• a colorless oil of 1-(1,2,3,4-tetrahydronaphthalen-2-­ylcarbonyl)-L-proline methyl ester was prepared in the same manner as Reference Example 1, except that 1,2,3,4-tetra­hydronaphthalen-2-ylcarboxylic acid was used instead of 2-indanylacetic acid and L-proline methyl ester was used instead of L-thioproline ethyl ester (yield: 63%).
• a colorless oil of 3-(6-methoxy-1,2,3,4-tetrahydro­naphthalen-2-ylacetyl)-L-thioproline ethyl ester was prepared in the same manner as Reference Example 1, except that 6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylacetic acid was used instead of 2-indanylacetic acid (yield: 80%).
• a colorless oil of 3-(5,7-dimethyl-1,2,3,4-­tetrahydronaphthalen-2-ylacetyl)-L-thioproline ethyl ester was prepared in the same manner as Reference Example 1, except that 5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-2-­ylacetic acid was used instead of 2-indanylacetic acid (yield: 51%).
• a colorless oil of 1-[(R)-(+)-1,2,3,4-­tetrahydronaphthalen-2-ylacetyl]-L-proline methyl ester was prepared in the same manner as in Reference Example 1, except that (R)-(+)-1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and L-proline methyl ester were used instead of 2-­indanyl acetic acid and L-thioproline ethyl ester, respectively (yield: 86%).
• a colorless oil of 3-[1-(2-indanylacetyl)-L-­prolyl]thiazolidine was prepared in the same manner as in Example 1, except that 1-(2-indanylacetyl)-L-proline was used instead of 3-(2-indanylacetyl)-L-thioproline (yield: 69%).
• a colorless oil of 1-[1-(2-indanylacetyl)-L-­prolyl]pyrrolidine was prepared in the same manner as in Example 1, except that 1-(2-indanylacetyl)-L-proline and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-­thioproline and thiazolidine, respectively (yield: 62%).
• a colorless oil of 3-[4-(2-indanylacetyl)-DL-1,4-­thiazan-3-ylcarbonyl]thiazolidine was prepared in the same manner as in Example 1, except that 4-(2-indanylacetyl)-DL-­1,4-thiazan-3-ylcarboxylic acid was used instead of 3-(2-­ indanylacetyl)-L-thioproline (yield: 84%).
• a colorless oil of 1-[4-(2-indanylacetyl)-DL-1,4-­thiazan-3-ylcarbonyl]pyrrolidine was prepared in the same manner as in Example 1, except that 4-(2-indanylacetyl)-DL-­1,4-thiazan-3-ylcarboxylic acid and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 62%).
• a colorless oil of 3-[1-(2-indanylacetyl)-DL-piperidin-­2-ylcarbonyl]thiazolidine was prepared in the same manner as in Example 1, except that 1-(2-indanylacetyl)-DL-piperidin-­2-ylcarboxylic acid was used instead of 3-(2-indanylacetyl)-­L-thioproline (yield: 71%).
• a colorless oil of 1-[1-(2-indanylacetyl)-DL-­piperidin-2-ylcarbonyl]pyrrolidine was prepared in the same manner as in Example 1, except that 1-(2-indanylacetyl)-DL-­piperidin-2-ylcarboxylic acid and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 68%).
• a colorless oil of 3-[1-(2-indanylacetyl)-L-piperidine-­2-ylcarbonyl]thiazolidine was prepared in the same manner as in Example 1, except that 1-(2-indanylacetyl)-L-piperidine-­2-ylcarboxylic acid was used instead of 3-(2-indanylacetyl)-­L-thioproline (yield: 72%).
• a colorless oil of 1-[1-(2-indanylacetyl)-L-piperidine-­ 2-ylcarbonyl]pyrrolidine was prepared in the same manner as in Example 1, except that 1-(2-indanylacetyl)-L-piperidine-­2-ylcarboxylic acid and pyrrolidine were used instead of 3-­(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 48%).
• a colorless oil of 1-[1-(2-indanylacetyl)-D-piperidine-­2-ylcarbonyl]pyrrolidine was prepared in the same manner as in Example 1, except that 1-(2-indanylacetyl)-D-piperidine-­2-ylcarboxylic acid and pyrrolidine were used instead of 3-­(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 91%).
• a colorless oil of 3-[1-(1,2,3,4-tetrahydronaphthalene-­2-ylcarbonyl)-L-prolyl]thiazolidine was prepared in the same manner as in Example 1, except that 1-(1,2,3,4-­tetrahydronaphthalen-2-ylcarbonyl)-L-proline was used instead of 3-(2-indanylacetyl)-L-thioproline (yield: 61%).
• a colorless oil of 1-[1-(1,2,3,4-tetrahydronaphthalene-­2-ylcarbonyl)-L-prolyl]pyrrolidine was prepared in the same manner as in Example 1, except that 1-(1,2,3,4-­tetrahydronaphthalen-2-ylcarbonyl)-L-proline and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 52%).
• a colorless oil of 3-[1-(1,2,3,4-tetrahydronaphthalene-­2-ylacetyl)-L-prolyl]thiazolidine was prepared in the same manner as in Example 1, except that 1-(1,2,3,4-tetrahydro­naphthalen-2-ylacetyl)-L-proline was used instead of 3-(2-­indanylacetyl)-L-thioproline (yield: 33%).
• a colorless oil of 3-[3-(2-indanylacetyl)-L-­thioprolyl]-L-thioproline ethyl ester was prepared in the same manner as in Example 1, except that L-thioproline ethyl ester was used instead of thiazolidine (yield: 75%).
• a pale yellow amorphous solid of 3-[1-(2-indenyl­acetyl)-L-prolyl]thiazolidine was prepared in the same manner as in Example 1, except that 1-(2-indenylacetyl)-L-­proline was used instead of 3-(2-indanylacetyl)-L-­thioproline (yield: 55%).
• a pale yellow amorphous solid of 1-[1-(2-indenyl­acetyl)-L-prolyl]pyrrolidine was prepared in the same manner as in Example 1, except that 2-(2-indenylacetyl)-L-proline and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-­thioproline and thiazolidine, respectively (yield: 62%).
• a colorless oil of 1-[3-(5-chloroindan-2-ylacetyl)-L-­thioprolyl]pyrrolidine was prepared in the same manner as in Example 25, except that 5-chloroindan-2-ylacetic acid was used instead of 3-(indan-2-yl)propionic acid (yield: 93%).
• Example 29 0.63 g of 1-[3-(5-nitroindan-2-ylacetyl)-L-thioprolyl]­pyrrolidine prepared in Example 29 was dissolved in a mixed solution of 9 ml of acetic acid and 6 ml of water. 1.00 g of iron powder was gradually added with stirring. After 1 hour, the iron powder was filtered. The filtrate was alkalinized using 10% sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate.
• a colorless oil of 1-[1-(6-methoxy-1,2,3,4-tetrahydro­naphthalen-2-ylacetyl)-L-prolyl]pyrrolidine was prepared in the same manner as in Example 1, except that 1-(6-methoxy-­1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-proline prepared in Reference Example 21 and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 24%).
• a colorless oil of 3-[1-(6-methoxy-1,2,3,4-tetrahydro­naphthalen-2-ylacetyl)-L-prolyl]thiazolidine was prepared in the same manner as in Example 1, except that 1-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-­proline prepared in Reference Example 21 was used instead of 3-(2-indanylacetyl)-L-thioproline (yield: 57%).
• a colorless oil of 1-[3-(6-methoxy-1,2,3,4-tetrahydro­naphthalen-2-ylacetyl)-L-thioprolyl]pyrrolidine was prepared in the same manner as in Example 1, except that 3-­(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-­thioproline prepared in Reference Example 23 and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 52%).
• a colorless oil of 3-[3-(6-methoxy-1,2,3,4-tetrahydro­naphthalen-2-ylacetyl)-L-thioprolyl]thiazolidine was prepared in the same manner as in Example 1, except that 3-­(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-­thioproline prepared in Reference Example 23 was used instead of 3-(2-indanylacetyl)-L-thioproline (yield: 67%).
• a colorless oil of 1-[3-(5,7-dimethyl-1,2,3,4-­tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]pyrrolidine was prepared in the same manner as in Example 1, except that 3-(5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-­L-thioproline prepared in Reference Example 25 and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-­thioproline and thiazolidine, respectively (yield: 60%).
• a colorless oil of 1-[1-(2-indenylacetyl)-L-prolyl]-L-­proline methyl ester was prepared in the same manner as in Example 1, except that 1-(2-indenylacetyl)-L-­proline and L-proline methyl ester were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 75%).
• a colorless oil of 1-[1-(2-indenylacetyl)-L-prolyl]-L-­prolyl]-L-prolinol was prepared in the same manner as in Example 20, except that 1-[1-(2-indenylacetyl)-L-prolyl]-L-­proline methyl ester was used instead of 1-[1-(2-­indanylacetyl)-L-proline methyl ester (yield: 58%).
• a colorless oil of 3- ⁇ 1-[(S)-(-)-1,2,3,4-tetrahydro­naphthalen-2-ylacetyl]-L-prolyl ⁇ thiazolidine was prepared in the same manner as in Example 25, except that (S)-(-)-­1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and 3-L-­prolylthiazolidine hydrochloride were used instead of 3-­(indan-2-yl)propionic acid and 1-L-thioprolylpyrrolidine hydrochloride, respectively (yield: 63%).
• Example 1 Compound of Example 2 50 g Lactose 315 g Corn starch 125 g Crystallized cellulose 25 g
• the above components were blended to obtain a homogeneous mixture.
• the mixture was made into granule by means of an extruding granulator using a screen with a 0.5 mm diameter.
• the granule was rounded and dried to produce a granulous preparation.
• the dried granule was coated with 1.9 kg of a film-coating liquid having the following composition using a fluid-type granulator to produce enteric coated granule.
• Example 2 Hydroxypropylmethyl cellulose phthalate 5.0 wt% Stearic acid 0.25 wt% Methylene chloride 50.0 wt% Ethanol 44.75 wt% Preparation Example 2 Compound of Example 18 20 g Lactose 100 g Corn starch 36 g Crystallized cellulose 30 g Calcium carboxymethyl cellulose 10 g Magnesium stearate 4 g
• the above components were homogeneously mixed and prepared into tablets each weighing 200 mg by means of a one-shot tablet machine using a 7.5 mm screw.
• Spray coating was applied to the tablets to prepare enteric film-coated tablets having the film weight of 10 mg per tablet.
• the composition of the coating liquid was as follows: Hydroxypropylmethyl cellulose phthalate 8.0 wt% Glycerol fatty acid ester 0.4 wt% Methylene chloride 50.0 wt% Breached beeswax 0.1 wt% Isopropanol 41.5 wt%
• the compounds of this invention exhibit both memory improving effects and cerebral circulation/metabolism improving effects because of their prolyl endopeptidase inhibitory activity, anti-hypoxic activity, and anti-amnesic activity.
• the compounds have a high degree of safety.
• they are useful as medicines for treating or preventing cerebral hemorrhage sequela, cerebral infarction sequela, cerebral arterioscleosis, subarachnoid hemorrhage sequela, cranial injury sequela, cerebral operation sequela, cerebrovascular dementia, Parkinson's disease, Alzheimer's disease, Pick's disease, various anoxia toxicosis including, but not limited to anthracemia sequela, cerebral alcoholoism related diseases, and the like.

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• Proteomics, Peptides & Aminoacids (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Plural Heterocyclic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Pyrrole Compounds (AREA)
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• 1989
  • 1989-11-28 CA CA002004028A patent/CA2004028C/en not_active Expired - Fee Related
  • 1989-12-01 US US07/444,702 patent/US5028604A/en not_active Expired - Lifetime
  • 1989-12-05 DE DE68919054T patent/DE68919054T2/de not_active Expired - Fee Related
  • 1989-12-05 EP EP89122394A patent/EP0372484B1/de not_active Expired - Lifetime
  • 1989-12-05 AU AU45914/89A patent/AU616824B2/en not_active Ceased
  • 1989-12-05 AT AT89122394T patent/ATE113279T1/de not_active IP Right Cessation
  • 1989-12-05 ES ES89122394T patent/ES2065975T3/es not_active Expired - Lifetime
  • 1989-12-07 DK DK616189A patent/DK616189A/da not_active Application Discontinuation

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